Orlistat, a tetrahydrolipstatin, is a useful pancreatic lipase-inhibiting agent and can be used for the prevention and treatment of obesity and hyperlipaemia. Chemically, orlistat is N-formyl-L-leucine [2S-[2alpha (R*), 3beta]]-1-[(3-hexyl-4-oxo-2-oxetanyl)methyl]dodecyl ester and is known from, for example, U.S. Pat. No. 4,598,089. It is represented by Formula I.

Processes have previously been reported for the preparation of orlistat, such as in U.S. Pat. Nos. 4,202,824; 4,983,746; and 4,931,463; J. Org. Chem., 53, (1988), 1218-1221; Tetrahedron Lett., 31, (1990), 3645-3648; Synlett., 11, (1991), 781-782; J. Org. Chem., 56, (1991), 4714-4718; J. Org. Chem., 58, (1993), 7768-7781; and J. Chem. Soc., Perkin Trans. 1, 17, (1998), 2679-2686.
U.S. Pat. No. 4,931,463 and WO 2005/005403 discloses the use of formic acid anhydride, acetic acid anhydride or a mixed acid anhydride such as formic acid/acetic acid anhydride for alkanoylating (S)-leucine (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl dodecyl ester (amino orlistat) of Formula II.
to produce orlistat.
It has been observed that there are certain disadvantages in using acetic anhydride and the mixed anhydride of formic acid/acetic acid anhydride as alkanoylating agents. In particular, formic acid/acetic acid anhydride used as alkanoylating agent leads to the formation of a by-product of Formula (III)
which is chemically N-(acetyl)-L-leucine (1S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester (deformyl-N-acetyl orlistat).
Therefore, there has been an ongoing research for new alkanoylating agents, which are capable of introducing the formyl group in good yield without producing by-products.
In their endeavor to find a simple, efficient, cost-effective process for the manufacture of orlistat in high yield and purity, the present inventors have found that the selection of alkanoylating agent during alkanoylation of amino orlistat influences the amount of by-products formed.